In normal intestinal epithelium, transforming growth factor-beta (TGFbeta) has been shown to act as a growth inhibitor. However, during the carcinogenic process, transformed cells become resistant to TGFbeta signaling, and TGFbeta then acts as a tumor promoter, presumably by enhancing tumor cell motility, angiogenesis and immunosuppression. TGFbeta1 is the TGFbeta isoform most frequently upregulated in tumor cells and somatic mutations in genes of the TGFbeta signaling pathway have been found in 80% of colorectal tumors. Thus, alterations in this pathway may play a role in colorectal neoplasia. Determinants of circulating concentrations of TGFbeta1 in healthy individuals are poorly understood, associations between genetic variants in this pathway and colorectal cancer risk have rarely been tested and the dual role of TGFbeta1 on tumor growth has not been considered in past epidemiological studies. The specific aims of the proposed research are three-fold: 1) To examine the associations of SNPs in the TGFbeta1 gene and lifestyle factors with circulating concentrations of TGFbeta1; 2) To determine haplotype blocks in genes of the TGFbeta signaling pathway (including TGFbeta1, TbetaR1, TbetaR2 and SMAD4), and select haplotype-tagging SNPs; and 3) To examine genetic variation (haplotypes and functional SNPs) in the TGFbeta signaling pathway and risk of colorectal neoplasia. These specific aims will be carried out using available samples and data from two complementary studies in the multi-ethnic population of Oahu, Hawaii. The first study is an ongoing, HMO-based case-control study of diet, genetic susceptibility and colorectal adenomas (544 cases, 817 controls). The other study is a completed population based case-control study designed to examine the relationship of diet and genetic susceptibility to colorectal cancer (548 cases, 656 controls). The proposed epidemiologic research is important in furthering our understanding of interindividual variation in TGFbeta signaling and its role in the etiology of human colorectal cancer, the third most common cancer in both sexes in this country.